The decline in DNA repair capacity contributes to the age‐associated decrease in genome integrity in somatic cells of different species. However, due to the lack of clinical samples and appropriate tools for studying DNA repair, whether and how age‐associated changes in DNA repair result in a loss of genome integrity of human adult stem cells remains incompletely characterized. Here, we isolated 20 eyelid adipose‐derived stem cell (ADSC) lines from healthy individuals (young: 10 donors with ages ranging 17–25 years; old: 10 donors with ages ranging 50–59 years). Using these cell lines, we systematically compared the efficiency of base excision repair (BER) and two DNA double‐strand break (DSB) repair pathways—nonhomologous end joining (NHEJ) and homologous recombination (HR)—between the young and old groups. Surprisingly, we found that the efficiency of BER but not NHEJ or HR is impaired in aged human ADSCs, which is in contrast to previous findings that DSB repair declines with age in human fibroblasts. We also demonstrated that BER efficiency is negatively associated with tail moment, which reflects a loss of genome integrity in human ADSCs. Mechanistic studies indicated that at the protein level XRCC1, but not other BER factors, exhibited age‐associated decline. Overexpression of XRCC1 reversed the decline of BER efficiency and genome integrity, indicating that XRCC1 is a potential therapeutic target for stabilizing genomes in aged ADSCs.

中文翻译：

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老年人类脂肪干细胞的碱基切除修复而不是DNA双链断裂修复受到损害。

DNA修复能力的下降导致不同物种的体细胞中与年龄相关的基因组完整性下降。然而，由于缺乏临床样本和研究DNA修复的适当工具，与年龄相关的DNA修复变化以及与之相关的人类修复干细胞基因组完整性丧失的方式仍不完整。在这里，我们从健康个体中分离了20个眼睑脂肪干细胞（ADSC）品系（年轻：10个捐献者，年龄在17-25岁之间；年龄：10个捐献者，年龄在50-59岁之间）。使用这些细胞系，我们系统地比较了年轻人和老年人之间碱基切除修复（BER）和两个DNA双链断裂（DSB）修复途径（非同源末端连接（NHEJ）和同源重组（HR））的效率。出奇，我们发现，在衰老的人ADSC中，BER而不是NHEJ或HR的效率受到损害，这与以前的发现相反，即人成纤维细胞的DSB修复随着年龄的增长而下降。我们还证明了BER效率与尾矩负相关，这反映了人类ADSC中基因组完整性的丧失。机理研究表明，在蛋白质水平上，XRCC1表现出与年龄相关的下降，而其他BER因素则没有。XRCC1的过表达逆转了BER效率和基因组完整性的下降，表明XRCC1是稳定老年ADSCs基因组的潜在治疗靶标。我们还证明了BER效率与尾矩负相关，这反映了人类ADSC中基因组完整性的丧失。机理研究表明，在蛋白质水平上，XRCC1表现出与年龄相关的下降，而其他BER因素则没有。XRCC1的过表达逆转了BER效率和基因组完整性的下降，表明XRCC1是稳定老年ADSCs基因组的潜在治疗靶标。我们还证明了BER效率与尾矩负相关，这反映了人类ADSC中基因组完整性的丧失。机理研究表明，在蛋白质水平上，XRCC1表现出与年龄相关的下降，但没有其他BER因子。XRCC1的过表达逆转了BER效率和基因组完整性的下降，表明XRCC1是稳定老年ADSCs基因组的潜在治疗靶标。